Hoebe, Kasper Project summary/Abstract: Th2 cells are central to the disease pathology of allergic asthma, however other T cell subsets play a disease- modifying role: Tregs limit asthma development, while Th17 cells and particularly pathogenic Th2/Th17 cells are associated with more severe disease. A key question remains how genetic alterations affect differentiation of T helper cells and contribute to asthma. Recently, a SNP in the GTPase of immunity-associated protein-5 (GIMAP5) were found to associate with increased asthma development. GIMAP5 is essential for peripheral lymphocyte survival and function; however, the underlying mechanism(s) and the biological function of GIMAP5 remain entirely elusive. Our new studies confirm the critical role for Gimap5 in allergic asthma, with Gimap5- deficient mice having significantly increased airway hyperresponsiveness (AHR), lung inflammatory cell infiltration upon house dust mite (HDM) challenge. Importantly, Gimap5-deficient mice progressively lose Treg function, cannot develop inducible Treg cells, and exhibit impaired T cell proliferation, while remaining CD4+ T cells are strongly skewed towards Th17 differentiation. When challenged with HDM, Gimap5-deficient mice develop a marked increase in pathogenic Th2/Th17 CD4+ T cells. Our new mechanistic data suggest that Gimap5 is essential for the inhibition of Glycogen Synthase Kinase-3 (GSK3)?a serine/threonine protein kinase whose inhibition is essential for the expression/activation of transcription factors required for T cell proliferation/differentiation. Importantly, pharmacological/genetic targeting of GSK3 completely recovers T cell survival/proliferation in Gimap5-deficient mice. These data support the overall hypothesis that loss of Gimap5 in CD4+ T cells promotes Th17/Th2 development at the expense of Tregs, thereby exacerbating asthma development. This will be tested in 2 independent yet interrelated aims using both mouse models and analysis of human sera from patients with allergic disease. Aim 1 will test the hypothesis that Gimap5 LOF exacerbates asthma by promoting the development of pathogenic Th2/Th17 cells at the expense of Treg cells, while aim2 will test the hypothesis that inhibiting GSK3 activity will prevent the skewing of Th2/Th17 differentiation away from Tregs that leads to severe allergic airway disease in Gimap5-deficient mice.